Pulmonary fibrosis contributes to morbidity and mortality in a wide spectrum of lung diseases. While it can result from environmental exposures or acute injuries, the events that initiate lung fibrosis are typically unknown. This Idiopathic Pulmonary Fibrosis (IPF) is the most common form of interstitial lung disease, and it is associated with a post-diagnosis survival of only 3 years. Despite decades of research, only 2 drugs are FDA approved to treat IPF, and both merely slow its progression. Failure to produce treatments to reverse or halt disease progression can be attributed to poorly understood IPF etiology. In turn, poor understanding can be attributed to an inability to detect and quantify early fibrosis and relate regional parenchymal remodeling to the functional, biomechanical, and molecular processes that initiate fibrosis. Eliminating this gap will require significant scientific and technical developments involving both biologically realistic disease models and sensitive and specific imaging technology. The long-term goal of this research is to quantify early pulmonary remodeling and relate it to profibrotic mecha- nisms and emergent pathophysiology. Our objectives in this application are to 1) determine the biophysical origin of magnetic resonance imaging (MRI) relaxation in fibrotic lung tissue, 2) quantify alveolar ventilation, 3) apply these metrics to two realistic, transgenic mouse models, and 4) extend quantitative ventilation MRI to IPF pa- tients. Our central hypothesis is that relaxation and ventilation will correlate with ex vivo measures of fibrosis (e.g., regional collagen content) and provide sensitive, noninvasive methods of quantifying fibrosis progression in vivo. Our rationale is that imaging markers?once validated in animal models and IPF patients?can readily be applied in mechanistic preclinical studies and in assessing IPF progression and therapy efficacy. Guided by strong preliminary data and theoretical work describing MR signal dynamics in the lungs, our central hypothesis will be tested by completing the following three Specific Aims: 1) validate transverse relaxation as a marker of lung fibrosis; 2) quantify impaired ventilation with multi-breath HP 129Xe washout; and 3) demonstrate the sensi- tivity of HP 129Xe washout MRI to impaired ventilation in IPF patients. Under Aim 1, we have developed the MRI sequences and reconstruction pipeline needed to complete the work. Under Aim 2, we have constructed and validated a hyperpolarized gas and MRI-compatible ventilator and developed the image processing tools to quantify regional tissue density. Under Aim 3, we have pioneered the use of efficient 3D spiral MRI sequences and keyhole-based image reconstruction to produce high-quality, quantitative human lung images. The proposed research is innovative both biologically and technically, because it will develop and validate noninvasive, regional measures of biophysical tissue properties and ventilation. These results are significant, because they will provide a means of detecting early pro-fibrotic events and noninvasively quantifying lung fibrosis progression. This work will have an immediate positive impact by allowing potential lung fibrosis therapies to be assessed and will pro- vide tools that can be translated into clinical use for evaluating disease progression and therapy response.